The tropomyosin receptor kinase (hereinafter abbreviated as “Trk”) family is classified as receptor tyrosine kinases and comprises TrkA which is a high-affinity receptor of nerve growth factor (hereinafter abbreviated as NGF), TrkB which is a high-affinity receptor of brain-derived neutrophic factor (BDNF) and neurotrophin (hereinafter abbreviated as NT)-4/5, and TrkC which is a high-affinity receptor of NT-3. All of the Trk receptors are highly expressed in nerve tissues and are involved in differentiation and maintenance of functions of nerve cells (see Non-Patent Document 1). Meanwhile, it has been known that activation of TrkA in peripheral nerves by NGF initiates hyperalgesia (see Non-Patent Document 2), and based on clinical and non-clinical test results using anti-NGF antibodies or non-clinical test results using low-molecular weight Trk inhibitors, involvement of TrkA has been reported in nociceptive pain of osteoarthritis, chronic low back pain, rheumatoid arthritis, bone fracture, interstitial cystitis, and chronic pancreatitis, neuropathic pain as well as cancer pain combining the both types of pain described above (see Non-Patent Documents 3 to 10). Moreover, the Trk receptors are expressed on cancer cells, such as neuroblastoma, thyroid cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, prostate cancer, etc., and a possibility of involvement in proliferation, migration, and metastasis of cancer cells is also reported. Especially, fused genes resulting from fusion of TrkA or TrkC with an MPRIP, CD74, TPM3, TPR, TFG, or ETV6 gene are discovered from a part of patients of thyroid cancer, lung cancer, breast cancer, colon cancer, or the like. It is reported that in the cancer having such a fused gene, the Trk kinase is always activated, and a compound having Trk-inhibiting activity inhibits the proliferation of cancer cells. In addition, the Trk receptor is also expressed in inflammatory cells, such as mast cells, eosinophils, etc., immunocompetent cells, such as T cells, B cells, etc., and keratinocytes, and so on, and is reported to be potentially involved in inflammatory diseases, such as ulcerative colitis, Crohn's disease, etc., allergic diseases, such as asthma, rhinitis, atopic dermatitis, and other diseases, such as psoriasis, (see Non-Patent Documents 11 to 15). Therefore, compounds having Trk-inhibiting activity may be possibly applied to therapy of nociceptive pain, neuropathic pain and pain combining the both types of pain, cancer, inflammatory diseases, allergic diseases, psoriasis, and so on.
In view of the foregoing, supposing that drugs capable of inhibiting Trk are created, it is expected that Trk-inhibitors may provide new types of prophylactic and/or therapeutic agents for pain and the like.
Meanwhile, Patent Document 1 discloses a method for treating or preventing a disease in a human or other mammal regulated by tyrosine kinase, comprising administering, to a human or other mammal in need thereof, a compound of the following formula (Ia), a salt thereof, an isomer thereof, or a prodrug thereof.
The general formula (Ia) is as follows:

In the formula,
Aa is selected from the group consisting of the following (i) to (iii) and the like:
(i) phenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen, and the like;
(ii) naphthyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen, and the like; and
(iii) a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms independently selected from the group consisting of O, N, and S, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen, and the like; and
Ba is selected from the group consisting of the following (i) to (iii) and the like:
(i) phenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —La-Ma, a C1-C5 linear or branched alkyl, a halogen, and the like;
(ii) naphthyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —La-Ma, a C1-C5 linear or branched alkyl, a halogen, and the like; and
(iii) a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms independently selected from the group consisting of O, N, and S, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —La-Ma, a C1-C5 linear or branched alkyl, a halogen, and the like;
La is selected from the group consisting of —(CH2)ma—O—(CH2)la—, —(CH2)ma—C(O)—(CH2)la—, and the like, wherein the variables ma and la are an integer independently selected from 0 to 4;
Ma is selected from the group consisting of the following (i) to (iii) and the like:
(i) phenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen, and the like;
(ii) naphthyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen, and the like; and
(iii) a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms independently selected from the group consisting of O, N, and S, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen, and the like;
wherein Ra1 is independently selected from the group consisting of (a) hydrogen, (b) a C1-C6 alkyl, (c) phenyl, (d) a 5- to 6-membered monocyclic heteroaryl or a 8- to 10-membered bicyclic heteroaryl, each having 1 to 4 hetero atoms selected from the group consisting of O, N, and S, (e) a C1-C3 alkyl-phenyl, and (f) an alkyl-heteroaryl having 1 to 4 hetero atoms selected from the group consisting of O, N, and S; and when Ra1 is not hydrogen, then Ra1 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C1-C5 linear, branched, or cyclic alkyl, a C1-C3 alkoxy, hydroxy, amino, a C1-C3 alkylamino, a C2-C6 dialkylamino, a halogen, cyano, and nitro; and the definitions of the groups are partially abstracted.
Patent Document 1 discloses that the compound therein inhibits KDR and is used for a method of treatment of diseases mediated by VEGF induced signal transduction pathways in a human or other mammals, particularly retinopathy or retinopathy of prematurity. However, it is neither disclosed nor suggested that the compound disclosed in the foregoing patent document has Trk-inhibiting activity, and the foregoing patent document does not specifically disclose the present compound, too.
In addition, Patent Document 2 discloses a Trk-inhibiting compound represented by the following formula (Ib) or a salt thereof and a drug containing the same as an active ingredient.
The general formula (Ib) is as follows:

In the formula,
the ring Cyb1 represents a C3-C10 monocyclic carbon ring or bicyclic carbon ring, or a 4- to 10-membered monocyclic heterocyclic ring or bicyclic heterocyclic ring; Rb1 represents a halogen, a C1-C6 alkyl group which may be substituted with a halogen, or the like; Rb2 represents (1) a C1-C6 alkyl group which may be substituted with a substituent selected from the group consisting of (i) a halogen, (ii) a hydroxyl group, and the like, (2) a hydrogen atom, (3) a hydroxyl group, (4) a carboxyl group, (5) an amino group, (6)
or the like; the arrow ab represents bonding to the ring Cyb1; Xb represents a bond, an oxygen atom, C═O, or NH; the ring Cyb2 represents a C3-C10 monocyclic carbon ring or bicyclic carbon ring, or a 4- to 10-membered monocyclic heterocyclic ring or bicyclic heterocyclic ring; Rb6 represents (1) a C1-C6 alkyl group which may be substituted with a substituent selected from the group consisting of (i) a halogen, (ii) a hydroxyl group, and the like, (2) a halogen, (3) a C1-C4 alkoxy group, or the like; Ab1 and Ab2 each independently represent ═CRb3—, ═CH—, or ═N—; Ab3, Ab4, Ab5, and Ab6 each independently represent ═CRb4— or ═N—; Rb3 represents a halogen or the like; Rb4 represents a halogen or the like; Yb represents an oxygen atom, a sulfur atom which may be oxidized, a methylene group, or C═O; Zb represents
or the like; Rb5 represents a halogen, a hydroxyl group, or a C1-C4 alkyl group which may be substituted with a hydroxyl group; Rb7s each independently represents a C1-C6 alkyl group which may be substituted with a substituent selected from the group consisting of a halogen, a hydroxyl group, and the like, a hydrogen atom, or the like; the arrows bb and cb, and the like represent bonding to the thiazole ring; pb represents an integer of 0 to 5; qb represents an integer of 0 to 7; rb represents an integer of 0 to 2; wb represents an integer of 1 to 5; and ub represents an integer of 0 to 2, provided that when pb, qb, rb, and ub each represent an integer of 2 or more, then Rb1, Rb6, Rb3, and Rb5 may be each independently the same as or different from each other; and the definitions of the groups are partially abstracted.
The Patent Document 2 discloses that this compound therein inhibits Trk, whereby it may become a prophylactic and/or therapeutic agent for pain and the like.
The present invention relates to an acid-addition salt of 1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea, 1-{2-[4-(2-amino-5-fluoropyridin-3-yl)phenoxy]pyrimidin-5-yl}-3-[2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl]urea, or 1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea, and any of the cited references neither disclose nor suggest that the foregoing acid-addition salt has a selective Trk-inhibiting action and persistently inhibits NGF vascular hyper permeability and does not have a drug interaction and in addition thereto, is excellent in solubility and absorbability against these free bases.